Transcript PPT - Larry Smarr - California Institute for Telecommunications and

“Reading Out the State of the Body
and How it Changes Under Therapy”
Guest Lecture
Pharmacy Informatics 2013
University of California San Diego
June 7, 2013
Dr. Larry Smarr
Director, California Institute for Telecommunications and Information Technology
Harry E. Gruber Professor,
Dept. of Computer Science and Engineering
Jacobs School of Engineering, UCSD
1
http://lsmarr.calit2.net
The Calit2 Vision of Digitally Enabled Genomic Medicine
is an Emerging Reality
2
July/August 2011
February 2012
Where I Believe We are Headed: Predictive,
Personalized, Preventive, & Participatory Medicine
I am Lee Hood’s Lab Rat!
www.newsweek.com/2009/06/26/a-doctor-s-vision-of-the-future-of-medicine.html
I Arrived
By Measuring
in La Jolla
theinState
2000of
After
My Body
20 Years
andin
“Tuning”
the Midwest
It
Using
and Decided
Nutrition
to and
Move
Exercise,
Against Ithe
Became
Obesity
Healthier
Trend
Age
41
Age
51
Age
61
1999
2000
1999
1989
I Reversed My Body’s Decline By
Quantifying and Altering Nutrition and Exercise
http://lsmarr.calit2.net/repository/LS_reading_recommendations_FiRe_2011.pdf
2010
Challenge-Develop Standards to Enable MashUps
of Personal Sensor Data Across Private Clouds
Withing/iPhoneBlood Pressure
FitBit Daily Steps &
Calories Burned
MyFitnessPalCalories Ingested
EM Wave PCStress
Azumio-Heart Rate
Zeo-Sleep
From Measuring Macro-Variables
to Measuring Your Internal Variables
www.technologyreview.com/biomedicine/39636
Visualizing Time Series of
150 LS Blood and Stool Variables, Each Over 5-10 Years
Calit2 64 megapixel VROOM
Only One of My Blood Measurements
Was Far Out of Range--Indicating Chronic Inflammation
Episodic Peaks in Inflammation
Followed by Spontaneous Drops
27x Upper Limit
Antibiotics
Normal Range<1 mg/L
Antibiotics
Normal
Complex Reactive Protein (CRP) is a Blood Biomarker
for Detecting Presence of Inflammation
Stool Samples Revealed
Episodic Autoimmune Response
124x Healthy
Upper Limit
Normal Range
<7.3 µg/mL
Antibiotics
Antibiotics
Lactoferrin is an Antibacteria Glycoprotein
Shed from Attacking WBC Neutrophils
Typical
Lactoferrin
Value for
Active
IBD
Colonoscopy Images Show
Inflamed Pseudopolyps in 6 inches of Sigmoid Colon
Dec 2010
May 2011
Confirming the IBD (Crohn’s) Hypothesis:
Finding the “Smoking Gun” with MRI Imaging
Liver
Transverse Colon
Small Intestine
I Obtained the MRI Slices
From UCSD Medical Services
and Converted to Interactive 3D
Working With
Calit2 Staff & DeskVOX Software
Descending Colon
MRI Jan 2012
Cross Section
Diseased Sigmoid Colon
Major Kink
Sigmoid Colon
Threading Iliac Arteries
MRE Reveals Inflammation in 6 Inches of Sigmoid Colon
Thickness 15cm – 5x Normal Thickness
“Long segment wall thickening
in the proximal and mid portions of the sigmoid colon,
extending over a segment of approximately 16 cm,
with suggestion of intramural sinus tracts.
Edema in the sigmoid mesentery
and engorgement of the regional vasa recta.”
– MRI report
Crohn's disease
affects the thickness
of the intestinal wall.
Having Crohn's disease
that affects your colon
increases your risk
of colon cancer.
Clinical MRI
Slice Program
DeskVOX 3D Image
Why Did I Have an Autoimmune Disease like IBD?
Despite decades of research,
the etiology of Crohn's disease
remains unknown.
Its pathogenesis may involve
a complex interplay between
host genetics,
immune dysfunction,
and microbial or environmental factors.
--The Role of Microbes in Crohn's Disease
So I Set Out to Quantify All Three!
Paul B. Eckburg & David A. Relman
Clin Infect Dis. 44:256-262 (2007)
I Wondered if Crohn’s is an Autoimmune Disease,
Did I Have a Personal Genomic Polymorphism?
From www.23andme.com
ATG16L1
Polymorphism in
Interleukin-23 Receptor Gene
— 80% Higher Risk
of Pro-inflammatory
Immune Response
IRGM
NOD2
SNPs Associated with CD
I am Now an Advisor
on the
23andme IBD Project
Autoimmune Disease Overlap
from SNP GWAS
Gut Lees, et al.
60:1739-1753
(2011)
Imagine Crowdsourcing 23andme SNPs
For Even a Small Portion of Crohnology!
www.crohnology.com
Crowd-Sourcing the Effectiveness
of Pharmaceutical Medications for Crohn’s Disease
www.crohnology.com
Fine Time Resolution Sampling Reveals Distinct
Dynamics of Innate and Adaptive Immune System
Normal
Normal
To Map My Gut Microbes, I Sent a Stool Sample to
the Venter Institute for Metagenomic Sequencing
Sequencing
Funding
Provided by
UCSD School of
Health Sciences
Shipped Stool Sample
December 28, 2011
I Received
a Disk Drive April 3, 2012
With 35 GB FASTQ Files
Weizhong Li, UCSD
NGS Pipeline:
230M Reads
Only 0.2% Human
Required 1/2 cpu-yr
Per Person Analyzed!
Gel Image of Extract from Smarr Sample-Next is Library Construction
Manny Torralba, Project Lead - Human Genomic Medicine
J Craig Venter Institute
January 25, 2012
Additional Phenotypes Added from NIH HMP
For Comparative Analysis
Download Raw Reads
~100M Per Person
35 “Healthy” Individuals
1 Point in Time
6 Ulcerative Colitis, 1 Point in Time
5 Ileal Crohn’s, 3 Points in Time
We Computationally Align 230M Illumina Short Reads
With a Reference Genome Set & Then Visually Analyze
~4500 Reference Genomes
with Strains and Viruses
Major Shifts in Microbial Ecology
in Health and Disease
Source: Weizhong Li, UCSD; Calit2 FuturePatient Expedition
LS
Crohn’s
Ulcerative
Colitis
Healthy
Toward Noninvasive
Microbial Ecology Diagnostics
We Can Measure the Changes in Microbial Ecology
Between Healthy and Two Forms of IBD
Microbiome “Dysbiosis”
or “Mass Extinction”?
Explosion of
Proteobacteria
On the IBD Spectrum
Collapse of
Bacteroidetes
Tracking How 1 Month Antibiotic, 2 Months Prednisone Therapy
Alters the Gut Microbial Ecology
Reduced 45x
Reduced 90x
Therapy Greatly Reduced Two Phyla,
But Massive Reduction in Bacteroidetes
And Large % Proteobacteria Remain
Small Changes
With No Therapy
How Does One Get Back
to a “Healthy” Gut Microbiome?
Intense Scientific Research is Underway
on Understanding the Human Microbiome
June 8, 2012
June 14, 2012
From Culturing Bacteria to Sequencing Them
2012 Was the Year
the Human Microbiome Entered the Public’s Mind
From War to Gardening:
New Therapeutical Tools for Managing the Microbiome
“I would like to lose the language of warfare,”
said Julie Segre, a senior investigator at
the National Human Genome Research Institute.
”It does a disservice to all the bacteria
that have co-evolved with us
and are maintaining the health of our bodies.”
Evidence for the Efficacy of Probiotics is IBD is Mixed More Clinical Research Needed
“...there is virtually no evidence of probiotic efficacy in Crohn’s disease.”
I Take a Probiotic “Cocktail”
to Enhance Microbial Diversity-48 Species of Bacteria
• Genera Covered:
–
–
–
–
–
–
–
–
Azospirillum
Azotobacter
Bacillus
Bacteriodes
Bifidobacteria
Brevibacterium
Kurtha
Lactobacillus
• Genera Covered:
–
–
–
–
–
–
–
–
Lactococcus
Leuconostoc
Myrothecium
Pediococcus
Phanerochaete
Pseudomonas
Streptococcus
Streptomyces
From the Single “Bad” Microbe Medical Target
to the Microbiome Ecology Paradigm
Sci Transl Med 4, 137rv5 (2012);
Science 336, 1255 (2012)
Problem of Alternative Stable States
In Ecological System Dynamics
Microbiome Transfer
May Be a Radical New Treatment for IBD
Procedures
Starting With
Natural Microbiome
Dr. Alexander Khoruts, NY Times
www.nytimes.com/2010/07/13/science/13micro.html
Next Steps:
Create
Synthetic Microbiomes
Tuned to the Patient
See
Microbiome 1:3 (2013)
Not FDA Approved Yet;
Increasing Number of Doctors Performing Procedure;
Clinical Trials Under Way;
Encouraging Results…
www.gihealthfoundation.org/reuters/articles.cfm?article=20111102drgd011
Next Decade Will See New Microbiome
“Gardening Tools”
August 7, 2012
Journal of Nanotechnology (2012)
Treating the Human Superorganism:
Your Body Has Ten Microbes for Every Human Cell!
Nature Reviews
Microbiology
v.9, p. 279 (2011)